The proposal has been amended in accordance with the suggestions of the Reviewers' and the study section. The objective of this research program is to provide the applicant with new and intensive training in immunology and to expand his research tools and expertise with the purpose of becoming an independent investigator. In order to achieve this goal, the applicant will train in the rich environment of the University of Alabama at Birmingham, under the joint mentorship of Judith Thomas, Ph.D., Anupam Agarwal, M.D., and Mark Atkinson, Ph.D. The overall unifying hypothesis of this application is that the product(s) of HO-1 activity is (are) necessary to attenuate processes leading to allograft rejection. The specific aims are: 1) To determine the mechanisms by which HO-1 regulates the recruitment and activation of monocytes/macrophages as well as their interaction with lymphocytes; 2) To determine the role of HO-1 activity on regulation of T cells and T cell-dependent B cell function; 3) To evaluate the role of HO-1 in islet allograft rejection. To accomplish these aims, a mouse model of HO-1 deficiency will be utilized and the effects of the products of HO-1 activity will be evaluated for their ability to reverse the changes attributed to HO-1 deficiency. The function of macrophages and lymphocytes will be studied both in vitro and in a model of islet transplantation. While contributing to the understanding of the rejection process and to development of targeted therapeutic approaches aimed at improving transplantation outcomes, the studies proposed in this application will be the basis for training the applicant in the state-of-the-art immunology techniques such as immune cell isolation and phenotyping, flow cytometry and cell sorting, ELISA and Luminex(r)-based assays of cytokines, adoptive transfer and functional studies of both cellular and humoral immune responses. This will greatly enhance the applicant's professional development towards becoming an independent researcher.